OCD is a severe, heritable condition with a lifetime prevalence of about two percent in world populations. The mode of inheritance is incompletely understood but is likely complex, involving multiple genetic loci of small to moderate effect. Our laboratory has played a leading role in studies of OCD and of its genetics for over 25 years, and was one of the founding sites of multi-center genome-wide studies of OCD, partial results of which have recently been reported in the group's publications noted below. In addition, a series of association studies that has identified and evaluated candidate genes in OCD and related disorders is continuing. In our Lab's continuing and collaborative investigations, we have also worked to clarify the fundamental phenotypical features of OCD and related disorders, sometimes designated 'OCD spectrum disorders', in reports published in 2011 and 2012. We are currently left with a multifaceted array of obsessive-compulsive features that cut across traditional diagnostic designations (DSM-IV) as well as draft plans for the DSM-V. In continuing efforts, our group and our collaborators have been using latent class modeling to go beyond factor and cluster analyses in order to parse OCD and related disorders into more valid groups. Considering underlying features, comorbid disorders (e.g., affective disorders), stressors and the other environmental events will provide additional elements to evaluate in these investigations. Examples of some sub-disorders that can contribute to OCD but can be found without classic OCD features include our recent and prior studies of hoarding and dystonias as well as of comorbid affective disorders, including bipolar disorder. The latter disorder is also under direct genetic study in continuing collaborative investigations. Studies of the role of serotonin, SLC6A4 and other major serotonin genes in OCD and related disorders such as Tourette disorder (in which &#61566;50% of patients meet diagnostic criteria for OCD). A manuscript was submitted in 2012 regarding the multiple SLC6A4 variants in Tourette Disorder. The strong relationship of SLC6A4 variants to different SRI treatment responses in humans represents an additional illustration of gene-based influences on serotonergic pharmacologic responses, i.e., a new SERT-based pharmacogenomics, directly relevant to the treatment of human neuropsychiatric disorders such as OCD and depression as well as to other serotonin-related human diseases. Recent evidence from treatment studies and genetic studies suggest that another neurotransmitter system may contribute to OCD. As with SERT in the serotonin system, the neuronal glutamate transporter is a major regulator of glutamate availability. This glutamate transporter is encoded by the gene SLC1A1 located within the chromosomal region 9p24. Recent evidence from 9p24 gene linkage analyses and candidate gene studies has suggested possible involvement of SLC1A1 in the development of OCD. Our large case-control study of SLC1A1 included over 950 OCD probands and controls collected by our Lab was published in 2011. In addition, SLC1A1 expression and genotype data were evaluated to gain further insights into SLC1A1 function. We found that gene expression of SLC1A1 is heritable in human cell lines. We identified three SNPs in or near SLC1A1 that correlated with gene expression levels. Additionally, two of these SNPs also predicted expression levels in human post-mortem brain tissue, and one SNP was found to have functional consequences in reporter gene studies. We are currently continuing further lab-based studies of this gene using transgenic techniques in mice and Dr. Moya from our Lab has created conditional Slc1A1 mice, one set of which has this gene deleted and another set which preferentially overexpresses this gene in the forebrain. The rational for creating these two opposite functional Slc1a1 mice was based on the equivocal findings from the human SLC1A1 studies regarding whether this gene might be hypofunctional or hyperfunctional in OCD. These investigations, taken together, indicate that SLC1A1, like SLC6A4, is a susceptibility gene for OCD. The expression and database-mining approach that we used provides a new and useful complementary model approach to strengthen future candidate gene studies in neuropsychiatric and other disorders which represent a large public health burden. In fact, seven neuropsychiatric disorders, including OCD, were listed in the 2001 World Health Organizations report on the leading causes of years of extended disability among adults. In additional studies of the genetics of OCD, we focused on candidate genes for OCD based on animal models of some OCD-related compulsive behaviors. These studies thus bring an even sharper focus on OCD subtypes or sub-populations that may be more closely related to specific single genes. In continuing studies based on this model, we are currently pursuing the first studies in humans, of the neuronal cadherin gene, CDH2, originally identified as an OCD candidate gene from an investigation of canine compulsive behaviors. We submitted our first full report on CDH2 in OCD in 2012. Also of note is that our group continues to share our 25+ year collection of DNA and phenotype data with collaborators in the Obsessive-Compulsive Disorder Collaborative Genetics Study (OCGS) and the Obsessive-Compulsive Foundation (OCF) groups, as well as with other intramural and extramural individual collaborators, thus enhancing the global search for underlying contributions to OCD and related disorders that are of major public health concerns. Papers that were published in the last year that are listed below resulted from these collaborative studies. The collaborative study to which our Lab contributed DNA and phenotype data based at Massachusetts General Hospital yielded a case-control genome association study involving 7022 individuals was published in 2012. One of the top signals obtained was in DLGAP1, coding a post-synaptic density (PSD) protein with high similarity to another PSD gene, DLGAP3 (SAPAP3) which we found to have rare variants enriched in OCD patients versus controls, as reported in a 2011 paper. The OCF collaborated GWAS was conceived complimentary one to the earlier OCGS family-based genome linkage study of 299 OCD-affected sibling pairs together with other family members constituting &#61566;11000 total individuals. This study generated 20 publications to date, the most recent in 2012. This 2012 study constituted fine mapping followed by SNP association studies of two regions identified in the initial linkage analysis. Associations were identified in or near a set of associated homeobox genes including MEIS2. Two of these form a heterodemeric complex. All three are involved in neurodevelopment and the heterodemeric complex is specifically known to affect development of the striatum, a brain region previously implicated in OCD via human brain imaging studies.